Chronic kidney disease (CKD) is increasingly prevalent in the elderly and carries sequelae that extend beyond progression to kidney failure. These sequelae include neurocognitive and physical dysfunction, both of which occur at markedly higher rates in CKD patients, even after accounting for differences in common co-morbidities including underlying cardiovascular disease and diabetes. Factors that may explain these impairments include endothelial dysfunction and inflammation, both of which are more frequent in CKD and are associated with cognitive and physical dysfunction in the general population. To date, no medical interventions have been shown to prevent cognitive and physical dysfunction in this exceedingly high-risk population. However, several pilot studies in individuals with CKD have examined the effect of exercise on physical performance, aerobic capacity, and health-related quality of life (HRQoL), suggesting that it may be possible to elicit functional improvements with supervised exercise training programs. Further, studies in healthy adults suggest aerobic exercise training may improve cognitive function, physical performance, vascular function, inflammation, and vascular risk factors. We hypothesize that exercise training will improve neurocognitive function, physical function, and health- related quality of life in older non-dialysis CKD patients, and that these results are mediated in part by improvements in inflammation, vascular function, lipids, blood pressure and insulin resistance. We propose a dual-center randomized parallel-group clinical trial to evaluate the effects of 12 months aerobic and resistance exercise training compared with directed health education control on neurocognitive function, physical performance, and HRQoL in 120 older community-dwelling adults with stage 3b-4 CKD. We will perform detailed measures at baseline and after 6 and 12 months of the following outcomes: 1) Neurocognitive tests of psychomotor speed, executive functions, and memory/learning;2) Aerobic capacity (peak V02);3) Physical performance including sub maximal walking speed, timed get up and go test, knee extensor strength, and short physical performance battery;4) HRQoL (Short Form-36);5) Microvascular function using laser Doppler flowmetry;6) Inflammation (hs-CRP and IL-6) and vascular risk factors (lipids, BP, insulin resistance). We will quantify the effects of exercise training on the primary outcomes, and examine exercise-related improvements of inflammation, microvascular function, and vascular risk factors as mediators of the beneficial effects of exercise on cognition and physical performance. We have assembled a multidisciplinary team for a cross-institutional collaboration of the NIA-funded Claude D. Pepper Older Americans Independence Centers affiliated with University of Maryland and Tufts University, which together have the resources and experience necessary to conduct a long-term exercise clinical trial. The results of this trial will be essential in identifying methods to improve functional status and ultimately prevent disability in this high-risk population. PUBLIC HEALTH RELEVANCE: Chronic Kidney Disease (CKD) is exceedingly common in older adults, in whom it is associated with impairment in cognition and physical function. The purpose of this study is to test the effects of 12 months aerobic and resistance exercise training compared to health education on cognitive and physical performance in 120 older adults with chronic kidney disease not requiring dialysis. The results of this study will be essential for demonstrating the effectiveness of exercise in improving function and ultimately preventing disability in this high-risk population of older adults.